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Papers of the Week

Papers: 1 Apr 2023 - 7 Apr 2023

Basic Science

In Vitro Studies, Molecular/Cellular


2023 Mar 30

J Biol Chem


Itch receptor MRGPRX4 interacts with the receptor activity-modifying proteins (RAMPs).


Kotliar IB, Ceraudo E, Kemelmakher-Liben K, Oren DA, Lorenzen E, Dodig-Crnković T, Horioka-Duplix M, Huber T, Schwenk JM, Sakmar TP


Cholestatic itch is a severe and debilitating symptom in liver diseases with limited treatment options. The class A G protein-coupled receptor (GPCR) Mas-related GPCR subtype X4 (MRGPRX4) has been identified as a receptor for bile acids, which are potential cholestatic pruritogens. An increasing number of GPCRs have been shown to interact with receptor activity-modifying proteins (RAMPs), which can modulate different aspects of GPCR biology. Using a combination of multiplexed immunoassay and proximity ligation assay we show that MRGPRX4 interacts with RAMPs. The interaction of MRGPRX4 with RAMP2, but not RAMP1 or 3, causes attenuation of basal and agonist-dependent signaling, which correlates with a decrease of MRGPRX4 cell surface expression as measured using a quantitative NanoBRET pulse-chase assay. Finally, we use AlphaFold Multimer to predict the structure of the MRGPRX4-RAMP2 complex. The discovery that RAMP2 regulates MRGPRX4 may have direct implications for future drug development for cholestatic itch.